3V4V

crystal structure of a4b7 headpiece complexed with Fab ACT-1 and RO0505376

Summary for 3V4V

• Entry DOI: 10.2210/pdb3v4v/pdb
• Related: 3V4P
• Descriptor: Integrin alpha-4, N-(2,6-dichlorobenzoyl)-4-[1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]-L-phenylalanine, Integrin beta-7, ... (11 entities in total)
• Functional Keywords: cell adhesion, madcam-1, membrane
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 342633.92

Authors

Yu, Y.,Zhu, J.,Springer, T.A. (deposition date: 2011-12-15, release date: 2012-01-11, Last modification date: 2024-10-30)

Primary citation

Yu, Y.,Zhu, J.,Mi, L.Z.,Walz, T.,Sun, H.,Chen, J.,Springer, T.A.
Structural specializations of a4b7, an Integrin that Mediates Rolling Adhesion
J.Cell Biol., 196:131-146, 2012

PubMed Abstract: The lymphocyte homing receptor integrin α(4)β(7) is unusual for its ability to mediate both rolling and firm adhesion. α(4)β(1) and α(4)β(7) are targeted by therapeutics approved for multiple sclerosis and Crohn's disease. Here, we show by electron microscopy and crystallography how two therapeutic Fabs, a small molecule (RO0505376), and mucosal adhesion molecule-1 (MAdCAM-1) bind α(4)β(7). A long binding groove at the α(4)-β(7) interface for immunoglobulin superfamily domains differs in shape from integrin pockets that bind Arg-Gly-Asp motifs. RO0505376 mimics an Ile/Leu-Asp motif in α(4) ligands, and orients differently from Arg-Gly-Asp mimics. A novel auxiliary residue at the metal ion-dependent adhesion site in α(4)β(7) is essential for binding to MAdCAM-1 in Mg(2+) yet swings away when RO0505376 binds. A novel intermediate conformation of the α(4)β(7) headpiece binds MAdCAM-1 and supports rolling adhesion. Lack of induction of the open headpiece conformation by ligand binding enables rolling adhesion to persist until integrin activation is signaled.

PubMed: 22232704
DOI: 10.1083/jcb.201110023

Experimental method

X-RAY DIFFRACTION (3.1 Å)